Compliance Risk Management Using a Top-Down Validation Approach 3

An example product applying the top-down approach

Figure 2

A sterile dry powder is filled into vials without excipients for later reconstitution with a sterile diluent (see Figure 2). The API is gamma-irradiated in bulk before the aseptic fill. The validation effort must support the methods and practices that ensure the product's critical quality attributes. In this example (and most others), it should be immediately evident that the various quality concerns will overlap to some extent. The critical quality attributes for this product (excluding the need for a sterile diluent, which should undergo a separate assessment) are:

• Safety—sterility, endotoxin control, foreign matter, container-closure integrity, residual solvent
• Purity—impurities, foreign matter, lack of cross-contamination
• Efficacy—particle size, crystal morphology, weight control, shipping studies
• Identity—chemical structure, labeling
• Strength—potency, stability.

Each of these primary considerations must be defined to identify the individual qualification or validation activities required to support the quality attribute in total. Product safety requires many studies, including:

• Aseptic filling capability
• Sterilization of bulk powder
• Sterilization or depyrogenation of glass containers and rubber closures
• Sterilization of product-contact equipment
• Sterilization of utensils
• Filling-isolator decontamination
• Environmental monitoring of the isolator environment
• Water for injection systems at API, and fill–finish facility (i.e., endotoxin control)
• Cleaning of API equipment
• Cleaning of fill–finish equipment
• Cleaning of empty bulk containers
• Cleaning of container or closure
• Bulk-container integrity
• Final product container-closure integrity
• Shipping studies
• Validation of API drying.

Product purity requires attention to:

• Impurity profiles
• API process validation
• API equipment cleaning
• Foreign-matter removal
• Absence of cross-contamination from prior products
• Cleaning validation for API
• Cleaning validation for fill–finish equipment
• Bulk-container preparation
• Container preparation
• Stopper washing
• Vial washing.

Efficacy mandates attention to:

• Particle size (i.e., crystallization process)
• Crystal morphology
• API process validation
• Suitability with filling equipment
• Weight control
• Filling equipment qualification
• Shipping studies
• Effect of pressure, temperature, and relative humidity
• Bulk-powder stability (pre and poststerilization)
• Filled-container stability.